Pre-procedural neutrophil-to-lymphocyte ratio and long-term cardiac outcomes after percutaneous coronary intervention for stable coronary artery disease

Accepted Manuscript Pre-procedural neutrophil-to-lymphocyte ratio and long-term cardiac outcomes after percutaneous coronary intervention for stable coronary artery disease Hideki Wada, Tomotaka Dohi, Katsumi Miyauchi, Jun Shitara, Hirohisa Endo, Shinichiro Doi, Hirokazu Konishi, Ryo Naito, Shuta Tsuboi, Manabu Ogita, Takatoshi Kasai, Ahmed Hassan, Shinya Okazaki, Kikuo Isoda, Satoru Suwa, Hiroyuki Daida PII:

S0021-9150(17)31229-7

DOI:

10.1016/j.atherosclerosis.2017.08.007

Reference:

ATH 15162

To appear in:

Atherosclerosis

Received Date: 1 June 2017 Revised Date:

12 July 2017

Accepted Date: 17 August 2017

Please cite this article as: Wada H, Dohi T, Miyauchi K, Shitara J, Endo H, Doi S, Konishi H, Naito R, Tsuboi S, Ogita M, Kasai T, Hassan A, Okazaki S, Isoda K, Suwa S, Daida H, Pre-procedural neutrophilto-lymphocyte ratio and long-term cardiac outcomes after percutaneous coronary intervention for stable coronary artery disease, Atherosclerosis (2017), doi: 10.1016/j.atherosclerosis.2017.08.007. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Pre-procedural neutrophil-to-lymphocyte ratio and long-term cardiac outcomes after percutaneous coronary intervention for stable coronary artery disease

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Hideki Wada a, Tomotaka Dohi a, Katsumi Miyauchi a, Jun Shitara a, Hirohisa Endo a, Shinichiro Doi a, Hirokazu Konishi b, Ryo Naito c, Shuta Tsuboi b, Manabu Ogita b, Takatoshi Kasai a, Ahmed Hassan

a,d

, Shinya Okazaki a, Kikuo Isoda a, Satoru Suwa b,

Department of Cardiovascular Medicine, Juntendo University Graduate School of

Medicine, Tokyo, Japan b

Department of Cardiovascular Medicine, Juntendo University Shizuoka Hospital,

Izunokuni, Shizuoka, Japan

Department of Cardiovascular Medicine, Juntendo University Urayasu Hospital,

Urayasu, Chiba, Japan

Department of Cardiology, Suez Canal University, Ismailia, Egypt

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c

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a

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Hiroyuki Daida a

Address for correspondence: Department of Cardiovascular Medicine, Juntendo

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University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.

E-mail: [email protected] (T. Dohi)

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Abstract

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Background and aims: An elevated neutrophil-to-lymphocyte ratio (NLR) has been associated with worse clinical outcomes in patients with acute coronary syndrome. However, the long-term prognostic value of NLR in stable coronary artery disease

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(CAD) after percutaneous coronary intervention (PCI) has not been fully investigated. The aim of this study was to determine whether NLR is an independent predictor of

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long-term cardiac outcomes after PCI.

Methods: A total of 2,070 patients with CAD who underwent elective PCI were enrolled in the study. Patients were divided into three groups by NLR tertile (<1.7, 1.7-2.5, and 2.5<). Incidences of all-cause death and cardiac death were evaluated.

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Results: During follow-up (median, 7.4 years), 300 patients (14.5%) died. Kaplan-Meier curves revealed ongoing divergence in rates of all-cause death and cardiac death among tertiles (both log-rank p<0.01). In multivariate analysis, using the lowest tertile as

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reference, the highest tertile remained significantly associated with greater incidences of all-cause death (hazard ratio (HR), 1.73; 95% confidence interval (CI), 1.29-2.34;

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p=0.0002). Continuous NLR values were also an independent predictor of all-cause death (HR, 1.87 per log NLR 1 increase; 95%CI, 1.50-2.32; p<0.0001) and cardiac death (HR, 2.11; 95%CI, 1.46-3.05; p<0.0001). Adding NLR values to a baseline model with established risk factors improved the C-index (p=0.002), net reclassification improvement (p=0.008) and integrated discrimination improvement (p=0.0001) for all-cause death. Conclusions: Elevated NLR was an independent predictor of long-term cardiovascular

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outcomes after elective PCI. Assessing pre-PCI NLR may be useful for risk stratification of stable CAD.

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Key Words: inflammation, atherosclerosis, coronary artery disease

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Introduction Inflammation plays an important role in the progression and destabilization of atherosclerosis [1]. White blood cells (WBC), particularly neutrophils, are useful

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inflammatory biomarkers associated with cardiovascular events [2]. On the other hand, low lymphocyte counts may reflect general stress and malnutrition, and have been associated with complications and poor mortality rates [3]. Recently, the

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neutrophil-to-lymphocyte ratio (NLR) has emerged as a potential inflammatory biomarker with predictive power for both cardiac and non-cardiac events [4-9].

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Furthermore, previous studies have shown that an elevated NLR in patients with acute coronary syndrome (ACS) was associated with adverse cardiac events after percutaneous coronary intervention (PCI) [10-13]. However, the prognostic values of pre-procedural NLR in patients with stable coronary artery disease (CAD) after PCI

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have not been fully investigated. The aim of this study was to determine whether pre-procedural NLR represents an independent predictor for long-term cardiac

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outcomes after PCI.

Patients and methods

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Study population and data collection The present investigation was a single-center, observational, retrospective

cohort study. Among consecutive patients with CAD, who underwent PCI for the first time at Juntendo University Hospital between January 2000 and December 2011, we excluded the patients without available data of NLR and patients with known malignancy or active inflammatory disease. NLR was calculated as the ratio of the neutrophil count to the lymphocyte count, with both values obtained from the same

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blood sample. Patients were divided into 3 groups according to the pre-procedural NLR (<1.7, 1.7-2.5, or >2.5). Blood samples were collected in the early morning after overnight fasting, and

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blood pressure (BP) was measured on admission. Hypertension was defined as BP >140/90 mmHg or receiving antihypertensive drugs. Patients with low-density lipoprotein cholesterol (LDL-C) ≥140 mg/dl, high-density lipoprotein cholesterol

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(HDL-C) ≤40 mg/dl, triglycerides ≥150 mg/dl, or current treatment with statins and/or lipid-lowering agents were regarded as dyslipidemia [14]. Diabetes mellitus was defined

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as either hemoglobin A1c ≥6.5% or medication with hypoglycemic drugs. Chronic kidney disease (CKD) was defined as an estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m2. Left ventricular ejection fraction (LVEF) was assessed using left ventricular angiography or echocardiography before PCI. All patients had symptoms of

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effort angina and/or proven myocardial ischemia according to noninvasive diagnostic tests.

Written, informed consent was obtained from all patients prior to PCI. This

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study was performed in accordance with the Declaration of Helsinki and with the

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approval of our institutional review board.

Primary endpoints

We evaluated both all-cause death and cardiac death. Cardiac death was

defined as death from CAD, cardiogenic shock, or sudden death. Clinical follow-up comprised analyses of clinical charts and responses to questionnaires sent to patients or their families and telephone contact.

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Statistical analysis Data are presented as mean ± standard deviation or median and interquartile range (IQR) for continuous variables. Categorical variables are presented as frequencies.

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Continuous variables across groups were compared using one-way analysis of variance or the Kruskal-Wallis test. The chi-squared test was used for categorical variables. NLR and biochemical and clinical measurements were used for simple linear regression

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analysis. Pearson’s correlation coefficients were used to examine relationships between NLR and other variables. Unadjusted cumulative event rates were estimated using

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Kaplan-Meier curves and a log-rank test was used to analyze the significant differences among groups. A logistic regression analysis and Cox proportional hazard analysis were used to determine the values of NLR. Hazard ratios (HRs) and confidence intervals (CIs) were calculated for each factor by a Cox proportional-hazards analysis. The

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C-index, net reclassification improvement (NRI), and integrated discrimination improvement (IDI) were calculated to assess whether the accuracy of predicting cardiac events would improve after adding NLR into a baseline model with established risk

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factors. Differences were considered significant at p<0.05. Statistical analyses were

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carried out using JMP version 12.0 software (SAS Institute, Cary, NC) and R version 3.2.3 (http://www.R-project.org/; R Foundation for Statistical Computing, Vienna, Austria).

Results Baseline and procedural characteristics Of the 2,092 patients who underwent elective PCI, pre-procedural NLR data were available for 2,070 patients (98.9%). For these patients, median and mean NLR

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were 2.0 (IQR: 1.5, 2.7) and 2.4±1.9, respectively. Clinical and procedural characteristics of these patients are shown in Table 1. Patients in the highest NLR tertile displayed a higher prevalence of female sex, hypertension, and chronic kidney disease

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(CKD), as well as lower body mass index (BMI), triglycerides, LVEF, and serum albumin levels on admission.

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Correlations between NLR and biochemical and clinical measurements

Correlations between NLR levels and white blood cell (WBC) count (r = 0.330,

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p<0.0001), eGFR (r = -0.162, P<0.0001), LVEF (r = -0.171, p<0.0001) and serum albumin (r = -0.276, p<0.0001) were significant, but relatively weak.

Clinical outcomes

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The median duration of follow-up was 7.4 years (IQR, 4.6-10.4 years). In total, 300 (frequency, 14.5%) all-cause deaths were identified during follow-up, including 94 (4.5%) cases of cardiac death. All-cause deaths and cardiac deaths among patients

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stratified by tertiles of NLR are presented in Fig. 1. Cumulative incidences of all-cause death and cardiac death increased clearly and significantly with higher tertiles of NLR

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(log-rank test, p<0.0001, 0.008, respectively). To determine the value of NLR, a multivariate logistic regression analysis was

conducted. The variables for which the unadjusted p value was <0.20 in univariate analysis were included in a multivariate model. For all-cause death, age, BMI, CKD, diabetes mellitus, LVEF and statin use were analyzed using a multivariate logistic regression model. The logarithm (log) of the NLR was included in the multivariate modeling. In the multivariate model for cardiac death, current smoking was added into

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these covariates. The NLR was an independent predictor of all-cause mortality (odds ratio, 1.85 per log NLR 1 increase; 95%CI, 1.42-2.41; p<0.0001) and cardiac death (odds ratio, 1.79; 95%CI, 1.20-2.66; p=0.004).

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Table 2 shows Cox proportional hazard analyses for all-cause death and cardiac death. In unadjusted Cox modeling, rates of all-cause death and cardiac death rose progressively with higher NLR tertiles (p<0.0001, 0.008 for trend, respectively).

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Variables showing values of p<0.20 on univariate analyses for all-cause death were age, BMI, CKD, diabetes mellitus, hypertension, multivessel disease, LVEF and use of

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statins. In addition to those, current smoking was identified as significant in univariate analyses for cardiac death. Multivariate Cox hazard analysis also showed that patients in the high NLR tertile exhibited higher frequencies of all-cause death compared with those in the low NLR tertile (HR, 1.73; 95% CI, 1.29-2.34; p<0.001). On the other hand,

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multivariate analysis for cardiac death did not show such a significant correlation. Table 3 summarizes the findings of multivariate Cox hazard regression analysis. Even after adjusting for other variates, increased log NLR was significantly associated with higher

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incidences of all-cause death (HR, 1.87 per log NLR 1 increase; 95%CI, 1.50-2.32;

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p<0.0001) and cardiac death (HR, 2.11; 95%CI, 1.46-3.05; p<0.0001).

Discrimination and reclassification of NLR The C-index for all-cause death was greater in the baseline model with NLR

compared with the baseline model alone (p= 0.002; Table 4). The NRI and IDI for all-cause death were also significantly increased after adding NLR to the baseline model.

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Discussion The major findings of the present study were as follows: 1) patients with high NLRs showed significantly higher incidences of all-cause death and cardiac death than

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other patients; 2) even after adjusting for important covariates, higher pre-procedural NLR was strongly associated with poorer long-term clinical outcomes in patients after elective PCI; and 3) addition of NLR to a clinical prediction model significantly

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improved risk prediction for mortality.

In the present study, patients in the higher NLR tertile had worse clinical status,

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such as hypertension, CKD or worse LVEF. However, even after adjusting these risk factors, the NLR values remained as an independent predictor of worse clinical events. One possible explanation is the various properties of neutrophils and lymphocytes. The WBC count, a well-known marker of inflammation marker, has been reported as an

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independent predictor of cardiovascular events, mortality and severity of atherosclerosis [8]. Home et al. evaluated the predictive ability of total WBC counts and WBC subtypes for risk of cardiac events among CAD patients. [2] They found high neutrophil counts

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and low lymphocyte counts provided greater predictive ability than total WBC counts, with the greatest risk prediction given by the NLR. Neutrophils secrete large amounts of

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inflammatory mediators and regulate the inflammatory response [15]. In addition, neutrophils reportedly make atherosclerotic plaque more vulnerable by releasing protective enzymes, myeloperoxidase and superoxide radicals [16]. On the other hand, lymphocytes represent the regulatory pathway of the immune system. In the acute setting of coronary events or other disease, low lymphocyte counts are a common finding during a stress response, secondary to increased corticosteroid levels that induce apoptosis [17, 18]. The combination of neutrophils and lymphocytes (that is, NLR)

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could thus provide more useful information for predicting cardiovascular events in CAD patients. NLR has been reported as a strong independent predictor of long-term clinical

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outcomes among ST-segment elevated myocardial infarction (STEMI) patients [12, 13, 19]. Furthermore, NLR is reportedly related to no-reflow and impaired myocardial perfusion in STEMI patients [20, 21]. However, few reports have focused on stable

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CAD or evaluated the usefulness of the NLRv [22]. Cho et al. investigated the combined usefulness of NLR and platelet-to-lymphocyte ratio (PLR) for predicting

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clinical outcomes in patients after PCIv [10]. In that report, high NLR and high PLR were independent predictors of long-term adverse outcomes among patients with ACS, whereas no clinical significance was seen among patients with stable angina. To the best of our knowledge, the present investigation is the first to find a long-term prognostic

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value of NLR in stable CAD patients after elective PCI. One of the features in the present study was a lower NLR than those reported from other investigations [23]. NLR is generally influenced by the condition or situation of the patient, and patients with

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ACS tend to have a higher NLR compared to patients with stable CAD [24]. However, even in stable CAD patients, previous studies have shown higher NLR. Horne et al.

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suggested NLR >4.71 as a cut-off for patients with stable CAD, using the highest quartile of NLR to define the value [2]. In the present study, the NLR for the highest tertile was >2.5, much lower than those cut-off values. The majority of the population in our study was ethnically Japanese, so racial differences in NLR might exist. An elevated NLR has been reported to correlate strongly with other inflammatory markers, such as the concentration of high-sensitivity C-reactive protein (hs-CRP) [25]. Interestingly, the present study found only a weak correlation between

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hs-CRP and NLR. Inflammation and atherosclerosis are closely related. Some studies have shown that the association between severity of atherosclerosis or CAD and NLR levels [24, 26-28]. In our study, although there were not any significant differences

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regarding reference vessel lumen diameter, stent size or proportion of LAD culprit lesion, the rate of multivessel coronary disease or left main trunk lesion was significantly increased with higher tertiles of NLR. These associations between

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atherosclerotic severity and NLR changes might affect clinical outcomes in patients after PCI.

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Numerous screening markers and scoring systems have been used for CAD patients, but some are relatively expensive or difficult to assess in daily clinical practice. NLR, simple, immediately obtained and inexpensive biomarker is useful to identify individuals at risk for adverse cardiac events. In the present study, we demonstrated that

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patients with NLR >2.5 had increased risk for cardiovascular events. Early risk stratification is important in the management of patients with CAD. Some medications, such as statins or antihypertensive therapies, have been reported to decrease NLR [29,

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30]. In addition, Wang et al. demonstrated that diet and exercise can improve NLR in overweight adolescents [31]. Few intervention studies have investigated patients with

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CAD and high NLR, but such treatments might improve NLR and clinical outcomes for CAD patients.

This study had several limitations. First, as a single-center, observational study

of a small patient cohort, unknown confounding factors might have affected the outcomes, regardless of analytical adjustments. Second, the present study evaluated NLR only once, and did not assess changes over time. Third, there are no any sufficient data about grade of pre- and post-PCI thrombolysis in myocardial infarction (TIMI)

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flow, severity of coronary lesion or procedural success. These might affect clinical outcomes in patients who underwent PCI. In conclusion, this study identified elevated NLR as an independent predictor

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of long-term cardiovascular outcomes after elective PCI. As a result, pre-procedural NLR may prove useful for risk stratification of stable CAD patients scheduled for PCI.

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Conflict of interest

with respect to this manuscript.

Author contributions

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The authors declared they do not have anything to disclose regarding conflict of interest

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H. Wada, T. Dohi and K. Miyauchi interpreted the data and drafted the manuscript. H.Wada, T. Dohi, J Shitara, H. Endo, S. Suwa and H. Daida conceived and designed the research. S. Doi, R. Naito, H. Konishi, S. Tsuboi, M. Ogita, A. Hassan, S.

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Okazaki and K. Isoda acquired and analyzed the data. H.Wada, T. Dohi and T. Kasai

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made critical revision of the manuscript. All authors revised the manuscripts.

Acknowledgments

We are grateful to the staff of the Department of Cardiovascular Medicine at

Juntendo University and the Department of Cardiology at Juntendo University Shizuoka Hospital. We also wish to express our appreciation for the secretarial assistance of Yumi Nozawa.

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Ridker, PM, Cushman, M, Stampfer, MJ, Tracy, RP and Hennekens, CH,

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[1]

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2011;32:982-986.

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Figure legends Figure 1. Kaplan-Meier curves of clinical outcomes categorized by NLR tertiles.

death.

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(A) Kaplan-Meier curves for all-cause death. (B) Kaplan-Meier curves for cardiac

Cumulative incidences of all-cause death (A) and cardiac death (B) increased clearly and significantly with higher tertiles of NLR (log-rank test, p<0.0001 and p<0.008,

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respectively). NLR, neutrophil-to-lymphocyte ratio.

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Table 4. Evaluation of predictive models for all-cause death. p

NRI (95%CI)

p

IDI (95% CI)

p

Established risk factors

0.700 (0.667−0.732)

Ref.

-

Ref.

-

Ref.

Established risk factors + NLR

0.716 (0.684−0.748)

0.002

0.16 (0.04−0.29)

0.008

0.02(0.01−0.03)

0.0001

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C-index (95% CI)

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Established risk factors included age, body mass index, chronic kidney disease, diabetes mellitus, hypertension, and use of statins. 95% CI, 95% confidence interval; IDI, integrated discrimination improvement; NLR, neutrophil-to-lymphocyte ratio; NRI, net reclassification

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improvement.

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Table 1. Clinical, angiographic and procedural characteristics in patients stratified by tertiles of neutrophil-to-lymphocyte ratio.

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NLR Tertile 1

Tertile 2

Tertile 3

(n = 2070)

<1.7

1.7-2.5

>2.5

(n = 729)

(n = 692)

(n = 649)

2.02 [1.50, 2.72]

1.36 [1.14, 1.53]

2.06 [1.87, 2.24]

3.19 [2.79, 4.01]

<0.0001

5811±1720

5281±1386

5681±1423

6544±2065

<0.0001

Neutrophils, %

59.4±9.4

49.9±5.4

59.8±3.2

69.5±6.1

<0.0001

Lymphocytes, %

29.8±8.7

38.9±5.1

29.2±2.4

20.2±4.5

<0.0001

Age, years

66.4±9.5

65.9±9.1

66.3±9.5

67.0±9.9

0.11

Male, n (%)

1716 (82.9)

580 (79.6)

580 (83.8)

556 (85.7)

0.008

Hypertension, n (%)

1516 (73.2)

510 (70.0)

525 (75.9)

481 (74.1)

0.04

Diabetes, n (%)

982 (47.4)

349 (47.9)

325 (47.0)

308 (47.5)

0.94

Dyslipidemia, n (%)

1520 (73.5)

543 (74.5)

518 (75.0)

459 (70.7)

0.16

Current smoker, n (%)

478 (23.1)

184 (25.3)

139 (20.2)

155 (23.9)

0.06

Family history, n (%)

592 (28.7)

220 (30.3)

206 (30.0)

166 (25.7)

0.13

Multivessel disease, n (%)

1250 (60.4)

411 (56.4)

438 (63.3)

401 (61.8)

0.02

24.2±3.4

24.6±3.4

24.3±3.5

23.7±3.2

<0.0001

182.5±36.0

185.9±35.6

182.5±35.6

178.7±36.5

0.001

110.1±30.8

111.8±31.0

110.6±30.3

107.8±31.0

0.05

HDL-C, mg/dl

44.6±13.4

44.8±13.1

44.9±13.8

44.3±13.4

0.68

TG, mg/dl

137.5±72.1

145.4±80.6

135.3±66.1

130.9±67.1

0.0006

White blood cells/µl

M AN U

NLR

TC, mg/dl LDL-C, mg/dl

EP

AC C

BMI, kg/m

TE D

Baseline characteristics

2

SC

Overall

p value

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109.1±32.8

108.8±32.9

107.9±28.7

110.9±36.6

0.24

HbA1c, %

6.4±1.2

6.4±1.3

6.4±1.2

6.3±1.2

0.22

0.10 [0.04, 0.21]

0.09 [0.04, 0.20]

0.09 [0.04, 0.22]

0.11 [0.05, 0.28]

<0.0001

4.0±0.4

4.1±0.4

4.0±0.4

3.9±0.5

<0.0001

eGFR, ml/min/1.73 m2

65.3±22.0

68.5±18.5

66.3±21.1

60.8±25.4

<0.0001

CKD, n (%)

713 (34.5)

215 (29.5)

224 (32.4)

274 (42.3)

<0.0001

HD, n (%)

129 (6.2)

20 (2.7)

37 (5.3)

72 (11.1)

<0.0001

Systolic blood pressure, mmHg

132.3±21.7

131.8±21.7

132.7±21.6

132.5±21.7

0.71

Diastolic blood pressure, mmHg

70.7±12.2

70.6±12.2

70.8±11.9

70.7±12.6

0.93

LVEF, %

62.7±12.1

64.6±11.2

62.5±11.5

60.7±13.3

<0.0001

LVEF <50%, n (%)

260 (13.6)

71 (10.4)

83 (13.0)

106 (18.1)

0.0004

Aspirin, n (%)

1936 (95.0)

688 (95.8)

646 (95.3)

602 (93.8)

0.21

ACE-I / ARB, n (%)

983 (48.2)

320 (44.6)

338 (49.9)

325 (50.6)

0.049

β-blocker, n (%)

1034 (50.7)

390 (54.3)

343 (50.6)

301 (46.9)

0.02

OHA, n (%)

630 (30.9)

229 (31.9)

199 (29.4)

202 (31.5)

0.55

Insulin, n (%)

257 (12.4)

84 (11.5)

78 (11.3)

95 (14.6)

0.12

Statin, n (%)

1178 (57.8)

420 (58.5)

415 (61.3)

343 (53.4)

0.01

926 (44.7)

314 (43.1)

325 (47.0)

287 (44.2)

0.32

64 (3.1)

16 (2.2)

19 (2.8)

29 (4.5)

0.048

2.87±0.51

2.87±0.52

2.84±0.51

2.89±0.49

0.11

3.0 [2.75, 3.5]

3.0 [2.5, 3.5]

3.0 [2.5, 3.25]

3.0 [2.75, 3.5]

0.19

Diseased LMT lesion, n (%) Reference lumen diameter, mm Stent size, mm

EP

AC C

LAD culprit coronary artery, n (%)

TE D

Medication

Lesion and procedure characteristics

SC

serum albumin, g/dl

M AN U

hs-CRP, mg/dl

RI PT

FBG, mg/dl

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1886 (91.1)

647 (88.8)

637 (92.1)

602 (92.8)

0.02

BMS use, n (%)

733 (35.4)

260 (35.7)

222 (32.1)

251 (38.7)

0.04

DES use, n (%)

1153 (55.7)

387 (53.1)

415 (60.0)

351 (54.1)

0.02

RI PT

Stent use, n (%)

ACE-I, angiotensin-converting enzyme inhibitors; ARB, angiotensin receptor blockers; BMI, body mass index; BMS, bare metal stent; CKD, chronic kidney disease; DES, drug-eluting stent; eGFR, estimated glomerular filtration rate; FBG, fasting blood glucose; HbA1c, hemoglobin A1c; HD,

SC

hemodialysis; HDL-C, high-density lipoprotein cholesterol; hs-CRP, high-sensitivity C-reactive protein; LAD, left anterior descending artery; LDL-C, low-density lipoprotein cholesterol; LMT, left main trunk; LVEF, left ventricular ejection fraction; NLR, neutrophil-to-lymphocyte ratio; OHA, oral

AC C

EP

TE D

M AN U

hypoglycemic agents; TC, total cholesterol; TG, triglycerides.

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Table 2. Cox proportional hazard model for all-cause death and cardiac death

HR

95% CI

p value

p value

for trend

HR

95% CI

p value

<0.0001 1.22

0.90-1.65

0.21

High tertile vs. low tertile

2.20

1.67-2.92

<0.0001

Adjusted model

M AN U

Intermediate tertile vs. low tertile

SC

Unadjusted model

Cardiac death

RI PT

All-cause death

1.17

0.85-1.61

High tertile vs. low tertile

1.73

1.29-2.34

1.56

0.92-2.70

0.10

2.23

1.34-3.79

0.002

0.25

0.33

1.47

0.84-2.61

0.18

0.0002

1.57

0.90-2.79

0.11

AC C

EP

TE D

Adjusted-for variables were age, body mass index, chronic kidney disease, diabetes mellitus, hypertension and statin use on admission. 95% CI, 95% confidence interval; HR, hazard ratio.

for trend 0.008

0.0006

Intermediate tertile vs. low tertile

p-value

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Table 3. Multivariable Cox proportional hazard model for all-cause death and cardiac death.

Cardiac death p value

Log NLR, 1 increase

1.87

1.51-2.32

<0.0001

Age, 1-year increase

1.04

1.03-1.06

<0.0001

BMI, 1-kg/m increase

0.95

0.92-0.99

0.02

CKD

1.48

1.16-1.89

0.002

2

Current smoking

HR

95% CI

p value

2.11

1.46-3.05

<0.0001

1.03

1.00-1.05

0.04

0.97

0.91-1.05

0.48

2.00

1.28-3.15

0.002

0.78

0.41-1.35

0.39

0.03

1.44

0.94-2.25

0.10

0.43

1.22

0.75-2.08

0.44

0.35

1.13

0.72-1.80

0.60

SC

95% CI

M AN U

HR

RI PT

All-cause death

1.30

1.03-1.65

Hypertension

1.12

0.85-1.48

Multivessel disease

1.12

0.88-1.45

LVEF, 10% increase

0.87

0.79-0.95

0.002

0.75

0.65-0.87

0.0001

Statin

0.59

0.46-0.75

<0.0001

0.66

0.43-1.02

0.06

TE D

Diabetes mellitus

AC C

neutrophil-to-lymphocyte ratio.

EP

95% CI, 95% confidence interval; BMI, body mass index; CKD, chronic kidney disease; HR, hazard ratio; LVEF, left ventricular ejection fraction; NLR,

AC C

EP

TE D

M AN U

SC

RI PT

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Highlights ・Patients with high neutrophil-to-lymphocyte ratio (NLRs) had higher incidences of

RI PT

cardiac events after elective percutaneous coronary intervention (PCI).

・Elevated NLR is an independent predictor of adverse outcomes after elective PCI.

SC

・NLR may prove useful for risk stratification of coronary artery disease (CAD) patients

AC C

EP

TE D

M AN U

scheduled for PCI.